VCV000025381.20 - ClinVar

NM_003060.4(SLC22A5):c.652+1G>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003060.4(SLC22A5):c.652+1G>A

Variation ID: 25381 Accession: VCV000025381.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q31.1 5: 132384302 (GRCh38) [ NCBI UCSC ] 5: 131719994 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 23, 2014	Feb 28, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003060.4:c.652+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001308122.2:c.724+1G>A		splice donor
NC_000005.10:g.132384302G>A
NC_000005.9:g.131719994G>A
NG_008982.2:g.19599G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000005.10:132384301:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA342640 dbSNP: rs386134200 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SLC22A5		-	-	GRCh38 GRCh37	1174	1217

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Renal carnitine transport defect	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000022334.27
Decreased circulating carnitine concentration	Pathogenic (1)	no assertion criteria provided	Mar 31, 2021	RCV002226445.9
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 19, 2023	RCV003329234.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renal carnitine transport defect Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893683.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jul 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renal carnitine transport defect Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835330.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Sep 19, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004036815.1 First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023	Comment: Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more) Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26828774, 28841266, 16602102, 17703373, 12210323) (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Renal carnitine transport defect Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000632561.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 16199547‚ 9916797‚ 12210323‚ 2235122 Comment: This sequence change affects a donor splice site in intron 3 of the SLC22A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects a donor splice site in intron 3 of the SLC22A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC22A5 are known to be pathogenic (PMID: 9916797). This variant is present in population databases (rs386134200, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with primary carnitine deficiency (PMID: 12210323). ClinVar contains an entry for this variant (Variation ID: 25381). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects SLC22A5 function (PMID: 2235122, 12210323). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 06, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Renal carnitine transport defect Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001363922.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (3) PubMed: 28841266‚ 12210323‚ 17703373 Comment: Variant summary: SLC22A5 c.652+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more) Variant summary: SLC22A5 c.652+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251494 control chromosomes (gnomAD). c.652+1G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Lamhonwah_2002, Hwu_2007, Frigeni_2017). These data indicate that the variant may be associated with disease. Two compound heterozygote patients were found to have significantly lower carnitine uptake/levels (Lamhonwah_2002, Hwu_2007). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Renal carnitine transport defect Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002055808.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022
Pathogenic (Mar 31, 2021)	no assertion criteria provided Method: clinical testing	Carnitine deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002078311.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
Pathogenic (Mar 31, 2021)	no assertion criteria provided Method: clinical testing	Renal carnitine transport defect Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002107434.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022

Comment:

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26828774, 28841266, 16602102, 17703373, 12210323)

Comment:

This sequence change affects a donor splice site in intron 3 of the SLC22A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC22A5 are known to be pathogenic (PMID: 9916797). This variant is present in population databases (rs386134200, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with primary carnitine deficiency (PMID: 12210323). ClinVar contains an entry for this variant (Variation ID: 25381). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects SLC22A5 function (PMID: 2235122, 12210323). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: SLC22A5 c.652+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251494 control chromosomes (gnomAD). c.652+1G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Lamhonwah_2002, Hwu_2007, Frigeni_2017). These data indicate that the variant may be associated with disease. Two compound heterozygote patients were found to have significantly lower carnitine uptake/levels (Lamhonwah_2002, Hwu_2007). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Functional and molecular studies in primary carnitine deficiency.	Frigeni M	Human mutation	2017	PMID: 28841266
Deficiency of the carnitine transporter (OCTN2) with partial N-acetylglutamate synthase (NAGS) deficiency.	Hwu WL	Journal of inherited metabolic disease	2007	PMID: 17703373
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy.	Lamhonwah AM	American journal of medical genetics	2002	PMID: 12210323
Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter.	Nezu J	Nature genetics	1999	PMID: 9916797
Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy.	Tein I	Pediatric research	1990	PMID: 2235122

Text-mined citations for rs386134200 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_003060.4(SLC22A5):c.652+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs386134200 ...